Micropthalmia-associated transcription factor (MITF) is an lineage-restricted, essential regulator of melanocyte survival and differentiation. In 15-20% of melanomas, MITF is amplified and is a behaves as a bone-fide oncogene: these melanomas are addicted to MITF activity, and suppression of expression or activity leads to cell cycle arrest, apoptosis and loss of tumorigenicity. Given its importance in melanocyte and melanoma biology, suppression of its activity may offer a novel therapeutic approach for the treatment of melanoma. The long-term GOAL of this research is to understand the signaling pathways that modulate MITF expression in the melanocyte lineage. Our CENTRAL HYPOTHESIS is that down-regulation of MITF may a therapeutic strategy for melanoma. Our OBJECTIVE is to identify small molecule suppressors of MITF using high throughput screening (HTS), with which to better understand the biological functions of MITF and to develop therapeutic agents for melanoma therapy. For this RO3 grant, we propose three SPECIFIC AIMS: (1) To perform a small molecule screen for modulators of MITF activity using cell-based luciferase reporter assays and (2) To perform secondary and (3) tertiary screens to validate activate compounds identified in Specific Aim 1. Although beyond the scope of this application, we will attempt to develop strategies for further refinement of the structure and function of active compounds. At the conclusion of the proposed project, we will be able to identify several highly active and specific suppressors of MITF with which to further investigate the biological functions of MITF. The identification of these compounds may also lead to development of novel therapeutic approaches for melanoma. PUBLIC HEALTH RELEVANCE: Identifying modulators of the micropthalmia-associated transcription factor (MITF) is critical to understand this master regulator of pigmentation and frequently mutated melanoma oncogene. Because modulation of MITF can be exploited for the treatment of melanoma, we expect that our screen will be relevant to the mission of NIH and will be interesting to both clinicians as well as researchers interested in the molecular pathogenesis of melanoma.